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2011INFORME_5

CONSEJERÍA DE SALUD

Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA)

Report on drug assessment

Eculizumab (Soliris)Assessment of effectivity and safety of the drug and economic analysis of use in Paroxysmal Nocturnal Haemoglobinuria therapy

Avda. Luis Montoto, 89. 4ª planta

41007 Sevilla-España (Spain)

Tlf.: 955 951 581 - Fax: 955 923 572

e-mail: [email protected]

Eculizumab (Soliris®)

Assessment of effectivity and safety of the drug and economic analysis of use in Paroxysmal Nocturnal

Haemoglobinuria therapy

Agencia de Evaluación de Tecnologías Sanitarias de Andalucía

www.juntadeandalucia.es/salud/aetsa

Avda. Luis Montoto, 89. 4ª planta

41007 Sevilla

España – Spain

Authors

Laila Abdel-Kader Martín. AETSA Technician. María Auxiliadora Castillo Muñoz. AETSA Technician. Emilio Jesús Alegre del Rey. Hospital Pharmacist. Hospital Universitario Puerto Real (Cádiz). Nuria Muñoz Muñoz. Hospital Pharmacist. Hospital Universitario Virgen Macarena (Sevilla). Juan Antonio Muñoz Muñoz. Haematologist. Haematology Department. Hospital Universitario Puerta del Mar (Cádiz), on behalf of the working group.

Conflict of interests

Authors declare no conflict of interest which could interfere with the primary interest and main goals in this final appraisal report on eculizumab.

One of the authors has received honoraria in the past for his contribution to symposiums organized by Alexion Pharma.

This report was finished in April 2010

Note to English translation:

Appendices to the original document have been not translated for the English version. Please, if necessary, consult the Spanish version.

Direction: Sandra Flores Moreno. Director of AETSA.

The following people have participated in this study:

Coordination of workgroup

Carmen Beltrán Calvo. Head of HTA Service, Andalusian Agency for Health Technology Assessment (AETSA). José Antonio Navarro Caballero. Economist. AETSA Operations Management Area and Health Economy Manager. José María Recalde Manrique. Director of CADIME.

Workgroup

Belén Corbacho Martín. Economist of AETSA. Jaime Espín Balbino. Economist. Professor of Escuela Andaluza de Salud Pública. Sergio Márquez Peláez. Economist of AETSA. Nieves Merino Kolly. Pharmacologist. Centro Andaluz de Farmacovigilancia. Álvaro Urbano Ispizua. Haematologist. Hospital Clinic (Barcelona).

Documentation

María Teresa Nieto Rodríguez. Technician of CADIME. Antonio Romero Tabares. Head of Servicio de Documentación e Información. AETSA.

External review

Ramiro Núñez Vázquez. Haematologist. Hospital Universitario Virgen del Rocío (Sevilla). Nuria Paladio Durán. Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM). José Luis Pinto Prades. Economist. Universidad Pablo de Olavide. Bernardo Santos Ramos. Hospital Pharmacist. Hospital Universitario Virgen del Rocío (Sevilla).

Organizations

Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA)

http://www.juntadeandalucia.es/salud/aetsa

Centro Andaluz de Documentación e Información de Medicamentos (CADIME)

http://www.easp.es/web/cadime/index.asp?idSub=303&idSec=303&idCab=303

Centro Andaluz de Farmacovigilancia (CAFV)

http://www.cafv.es/

Asociación Andaluza de Hematología

http://www.aa-hh.org/fundacion.php

Sociedad Andaluza de Farmacéuticos de Hospital (SAFH)

http://www.safh.org

http://www.juntadeandalucia.es/salud/aetsa

http://www.easp.es/web/cadime/index.asp?idSub=303&idSec=303&idCab=303

http://www.cafv.es/

http://www.aa-hh.org/fundacion.php

http://www.safh.org/

Contents

Abbreviations ...................................................................................................7

Executive summary .........................................................................................9

Introduction ....................................................................................................15

Description of paroxysmal nocturnal haemoglobinuria ..............................15

Justification ................................................................................................17

Main objectives ..........................................................................................19

Secondary objectives.................................................................................19

Metodology ....................................................................................................21

Systematic review of literature: efficacy and safety ...................................21

Systematic review of economic evaluation literature .................................22

Selection, evaluation of quality, and synthesis of literature of efficacy, safety, and economics............................................................................................22

Results of efficacy and safety bibliographic search ...................................25

Description of the documents included in the systematic review of efficacy and safety ...............................................................................................................26

Quality assessment of the studies .............................................................27

1. Baseline characteristics of patients included in the studies...................28

2. Intervention in the studies ......................................................................29

3. Main results of efficacy and safety.........................................................30

Economic evaluation results..........................................................................45

A. Review of the literature on economic aspects.......................................45

B. Critical analysis of information submitted by the company ...................47

C. Economic analysis de novo...................................................................48

Discussion .....................................................................................................53

1. Efficacy and safety systematic review discussion .................................53

2. Review of the economic analysis...........................................................56

Conclusions ...................................................................................................59

Recommendations.........................................................................................61

References ....................................................................................................63

Tables and figures

Table 1. Summary of characteristics of Eculizumab drug.....................................17 Table 2. Baseline characteristics of patients included in the pilot study

(phase II), TRIUMPH and SHEPERD ...................................................28 Tabla 3. Adverse events most frequently observed in the studies .......................34 Table 4. Summary of studies results.....................................................................36 Table 5a. Phase II study, Hillmen et al. 2004 (14). Most relevant aspects of

Phase II study........................................................................................37 Table 5b. Phase II study, Hillmen et al. 2004 (14). Measured variables ..............37 Table 6a. Extension study of phase II study, Hill et al. 2005 (15). Most

relevant aspects of Phase II study ........................................................38 Table 6b. Extension study of phase II study, Hill et al. 2005 (15). Variables........38 Table 7a. TRIUMPH randomised clinical trial (8;16). Most relevant aspects

of study..................................................................................................39 Table 7b. TRIUMPH randomised clinical trial (8;16). Variables............................40 Table 8a. SHEPHERD study (17). Most relevant aspects of study ......................41 Table 8b. SHEPHERD study (17). Variables ........................................................41 Table 9a. Extension study by Hillmen et al. 2007 (18). Most relevant

aspects of study ....................................................................................42 Tablee 9b. Extension study by Hillmen et al. 2007 (18). Variables ......................43 Table 10. Cost per PRBN avoided according to the study TRIUMPH..................50 Table 11. Cost per PRBN avoided according to the study SHEPHERED............50 Table 12. “Scenarios” of eculizumab use..............................................................51 Table 13. Number of cases and scenarios impact................................................51 Table 14. Annual savings for each scenario .........................................................52

Figure 1. Flowchart illustrating selection process of documents for the systematic review..................................................................................25

Figure 2. Flowchart showing eculizumab studies undertaken in patients with PNH ..............................................................................................27

Eculizumab for treatment of PNH / AETSA 2011

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Abbreviations

AAH Andalusian Hematology Association

AATRM Catalan Agency for Health Information, Assessment and Quality

ADIS AdisInsight

AERS Event Reporting System

AETSA Agency for Health Technology Assessment

AEs Adverse events

AUC Area under Curve

BOJA Official Journal of the Andalusian Regional Government

MAVE Major vascular events

AWMSG All Wales Medicines Strategy Group

CADIME Andalusian Drug Documentation and Information Center

CADTH Canadian Agency for Drugs and Technologies in Health

CAFV Andalusian Pharmacovigilance Center

CASPe Critical Appraisal Skills Programme (CASP)

CRD Center for Reviews and Dissemination

EMA European Medicines Agency

EORTC European Organization for Research and Treatment of Cancer EPAR European Public Assessment Report

FACIT Functional Assessment of Chronic Illness Therapy

FDA Food and Drug Administration

GENESIS Assessment of new drug approvals, standardization and research in drug selection Group

GPI Glycosylphosphatidylinositol

Hb Hemoglobin

HPP Hospital Purchase Price

IDIS Iowa Drug Information Service

IPA International Pharmaceutical Abstracts Database

ITT Intent to treat

LDH Lactate dehydrogenase

MAVEs Major adverse vascular events

NICE National Institute for Clinical Excellence

AETSA 2011 / Eculizumab for treatment of PNH

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NNT Number needed to treat

PMN Polymorphonuclear

PNH Paroxysmal Nocturnal Haemoglobinuria

PRBC Packed Red Blood Cells

PRBCU Packed Red Blood Cells Units

QALY Quality-adjusted life year

QLQ-C30 Quality of Life Questionnaire Core 30

RCT Randomised controlled trial

RPI Retail Price Index

SAEs Serious adverse events

SAFH Andalusian Society of Hospital Pharmacists

SAS Andalusian Health Service

SD Standard Deviation

SEFH Spanish Society of Hospital Pharmacy

SSPA Andalusian Health Public System

ULN Upper Limit of Normal

RUD Rational Use of Drugs

VAT Value-added Tax


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Executive summary

Introduction

Paroxysmal Nocturnal Haemoglobinuria (PNH) is a rare, acquired disorder, which affects pluripotential haematopoietic stem cells. Incidence rate has been reported in 0.13 cases per 100,000 inhabitants. Survival has been estimated as 10-15 years, with death occurring primarily due to thromboses, besides infections and haemorrhages.

Primary goals

• Evaluate clinical efficacy of eculizumab in the treatment of patients with PNH in terms of survival, thromboembolic events, quality of life, packed red blood cells (PRBC's) transfusions, hemoglobin levels, and haemolysis.

• Evaluate efficacy and safety of eculizumab in patients with PNH.

• Provide an economic analysis of eculizumab regarding cost effectiveness ratios in patients suffering PNH.

Secondary goals

o Evaluate safety of eculizumab treatment in patients with PNH de novo.

o Evaluate efficacy and safety of eculizumab treatment in patients with PNH who are under 18.

o Evaluate efficacy and safety of eculizumab treatment in cases of patients receiving again eculizumab treatment after withdrawal.

o Evaluate efficacy and safety of eculizumab treatment in patients with PNH, during pregnancy.

Methodology

A multidisciplinary work panel of experts was constitued in order to elaborate an evaluation report on eculizumab.

To accomplish evidence-based response to effectiveness and safety objectives, an exhaustive search of the published literature in referential data sources was performed.

Papers included in the efficacy and safety systematic review were studies regarding patients with PNH under eculizumab treatment. In these cases survival, thromboembolic events, quality of life, packed red blood cells (PRBC's) transfusions, hemoglobin levels, haemolysis, and safety were evaluated. Included studies were metanalysis, systematic reviews, clinical trials (RCTs), EMA’s evaluation report, cohort studies, and series of cases with a number of patients equal or superior to 10.

Articles included in the economic analysis literature review were economic reports


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and studies of health technology assessment.

Systematic reviews quality evaluation, RCTs, and economic studies quality evaluations were performed by means of CASPe questionnaires of literature critical reading. An specific questionnaire by panel methodologists was used for the critical evaluation of non-randomised intervention studies.

Efficacy and safety evaluation results

In the systematic review the following documents were included: a systematic review, eculizumab EMA’s European Public Assessment Report (EPAR), and five clinical studies evaluating the efficacy and safety of eculizumab in a total number of 195 patients with PNH [a pilot study in phase II and its extension, a randomised clinical trial (RCT) and two non-randomised intervention studies]

The systematic review results are presented below:

There is no evidence that eculizumab treatment improves survival in patients with PNH.

An uncontrolled intervention study evaluated the incidence of thromboembolic events in patients with PNH under eculizumab treatment. The effect of thromboembolic events minimized from 7.37 to 1.07 events/ 100 patients per year (p< 0.001).

Patient’s quality of life improvement was evaluated in the pilot study, its extensions, the TRIUMPH RCT, and the SHEPHERD study. It was measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Only in the phase II study the baseline scores were indicated in the EORTC QLQ-C30 scale.

In the TRIUMPH RCT, the 53.7% of patients of eculizumab group with respect to the 20.5% of the placebo group showed a change on the FACIT-Fatigue scale of 4.0 points, minimum clinically important difference (p=0.0028).

In most items showed in EORTC QLQ-C30 scale, there were significant differences both in the TRIUMPH RCT and the SHEPHERD study.

The median of PRBC's was equal to 0 in the group under eculizumab treatment compared to 10 in the placebo group (p<0.001), according to TRIUMPH RCT. In the same way, in the SHEPHERD study, the median of PRBC's before eculizumab treatment was reduced from 8 to 0 PRBC's after 12 months of treatment (p< 0.001).

Patients of TRIUMPH RCT were stratified at randomisation in three levels (4-14, 15-25 and > 25 PRBC's), according to the PRBC's units transfused in the previous year. After a 26-week treatment, differences among the median of PRBC's transfused in the eculizumab group and the placebo group was of 6.8 and 15 PRBC's (p< 0.005), respectively.

In the SHEPHERD study, patients were stratified according to the baseline LDH levels (537-1,379, 1,380-2,050, 2,051-2,866 and 2,867-5,245 U/L). The difference between PRBC's units transfused before and after the eculizumab treatment was: 8 (p= 0.143), 6.5 (p= 0.033), 9 (p<0.001) and 6.5 PRBC's (p=0.006), respectively.

51% of patients who received eculizumab, compared to 0% of the placebo group,


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in the TRIUMPH RCT, achieved transfusion independence over the 26 week-treatment (p<0.001).

Reduction of haemolysis was evaluated by means of the LDH levels. These levels decreased significantly after eculizumab treatment and remained stable during the study (p< 0.001).

With regards to eculizumab safety, the most serious adverse event considered to be treatment-related was meningococcal infection reported in 0.3% of eculizumab-treated patients.

In the TRIUMPH RCT, no significant differences were reported in relation to the frequency of adverse events between both treatment groups. In the SHEPHERD study, percentage of patients with adverse effects was 7.2%.

Economic evaluation results

Three reports have been included: two of them for the National Health Service (NHS), and one for the Andalusian Public Health System (SSPA). In all the cases no evidence was found to estimate cost-effectiveness in terms of quality adjusted life year (QALY), and when analytic models were build to calculate the estimation, the incremental cost per QALY gained is considered too superior compared with regular cost-effectiveness according to public health systems.

The economic analysis undertaken has evaluated the cost-effectiveness ratios of the effectiveness, making different assumptions. Cost-effectiveness ratios obtained are: the annual cost to improve patients’ quality of life after six months, measured by FACIT-Fatigue scale (1,500,000€/year); the annual cost for averting thrombosis in the course of a year (over 6,000,000€ minimum); and the cost of averted PRBC units within the range 13,125 to 19,669€, depending of the PRBC units previously required by each patient.

The SSPA (Andalusian Public Health System) annual cost estimation for provision of the drug, according to the number of patients, would be around 2,263,092 and 17,350,372€, with a reduction of budget impact estimated in 7,978.79 to 67,967.44€, due to reduced costs associated with a reduction in the transfusion of PRBC units.

Conclusions:

There is no evidence that eculizumab improves survival in PNH patients.

Evidence of eculizumab is not of sufficient quality. As a result of this, it is impossible to arrive at definite conclusions about the reduction of thromboembolic events in PNH patients. It is necessary to develop high quality studies contributing to solid evidence regarding this matter.

Half of PNH patients receiving eculizumab treatment show FACIT-Fatigue scores increased (improved) by four points in this instrument scale, especially when related to fatigue grade (minimum clinically important difference in quality of life).

Eculizumab treatment in PNH patients reduced the number of PRBC units transfused compared with placebo. Patients requiring less PRBC transfusions are


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the more severely affected patients or the moderate affected (depending on pre-treatment transfusion requirements and haemolysis).

Eculizumab treatment in PNH patients diminishes haemolysis (measured by LDH levels). The reduction in LDH levels with eculizumab commenced within one month and levels remain constant during the treatment period.

Eculizumab treatment is generally well tolerated.

Patients following therapy with eculizumab show a higher incidence of N. meningitidis compared with general population. In consequence, must be vaccinated when receiving eculizumab. However, the vaccine is not effective against serogroup B of Neisseria meningitidis, being this the most prevalent serogroup in Spain, and the one producing more infections.

There is no evidence of long-term safety of eculizumab in PNH patients.

There is no evidence regarding efficacy and safety when resuming eculizumab treatment after withdrawal in PNH patients.

There is no quality evidence allowing recommendations for eculizumab usage in PNH patients during pregnancy.

There is no evidence of efficacy and safety regarding eculizumab treatment in PNH patients under 18.

No evidence was found for the use of eculizumab in patients with PNH de novo (patients without previous transfusions).

Lack of information related to drug effectiveness means implementation of a full economic assessment for estimation of cost-effectiveness and/or cost-utility is impractical at this time.

The budget impact for the SSPA varies according to the different scenarios of cases for treatment and was estimated between 0.07% and 0.5% of total hospital expenditure.

As there is no scientific evidence regarding survival of treated patients, but just improvement in surrogate endpoints, it is not possible to calculate a model for estimation of cost in terms of QALY. According to a theoretical exercie based on significant assumptions, a cost per LYG will exceed between two and six times the highest estimations for ultra-orphan drugs as advised by NICE.

Cost-efficacy ratios estimated for surrogate endpoints of major clinical relevance show very high values (exceeding the highest estimations advised by NICE for this type of drug in terms of the incremental cost per QALY, which could serve as reference).

Recommendations:

■ The use of eculizumab in PNH patients when there is no clinical evidence should be considered as experimental. These situations include at this moment: patients without a history of transfusions, patients under 18, pregnant patients, and cases of


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patients who recommence eculizumab treatment after withdrawal.

Given that there is only solid evidence of eculizumab efficacy in surrogated endpoints, transfused PRBC units, and LDH levels, these outcomes should guide the criteria that define those patients who would qualify for eculizumab treatment. There is solid evidence that only patients with a greater history of transfusions in the previous year and higher LDH baseline levels, show major clinical benefit and better relation cost-efficacy. In consequence, those should be the criteria to select subgroups which potentially will obtain more benefit from treatment. For the rest of patients supportive treatment and monitoring are recommended.

In areas where there is uncertainty about eculizumab efficacy, being it measured in terms of health-related outcomes (f. e. efficacy in rates of thrombosis), it is recommended to establish an agreement based on shared risks with the manufacturing laboratory.

It is necessary for all patients who enroll for eculizumab treatment to accomplish the Risk Management Plan designed by the EMA for this drug.

It is recommended to undertake an evaluation of efficacy and safety after 3 months of treatment. In this initial evaluation, LDH levels will indicate eculizumab efficacy. In those patients in which eculizumab is not effective and/or safe, it is recommended to withdraw treatment.

Patients in whom treatment seems to be effective after the three first months should continue periodic monitorisation every six months. The following parameters should be registered: thrombotic events (type and location), number of RBC units transfused, biochemical parameters (LDH and creatinine), hemograma, infections (type and location), disease evolving towards other haematologic pathologies (aplastic anemia, leukaemia or myelodysplasic syndromes), adverse events, and spontaneus remission. Patients for whom eculizumab is not effective and/or safe are recommended to withdraw from treatment.

It is recommendable that the SSPA creates a group for the granting of centralised authorisation for this treatment. The group should apply the resolution established by the SAS management, individually, to each potential case. In the same way this group will be responsible for management of patients’ monitoring.

In addition, it is recommended the foundation of a PNH registry in Andalusia.


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Introduction

Description of paroxysmal nocturnal haemoglobinuria

Epidemiology of PNH

Paroxysmal Nocturnal Haemoglubinuria (PNH) is a rare disease, genetically acquired, which affects pluripotent hematopoietic cells. Incidence is estimated in 0.13/100,000 inhabitants (1). PNH is a chronic illness affecting mainly young adults of both sexes (2).

In Andalusia, real prevalence of this disease is unknown. Notwithstanding, according to information provided by clinical consultants, there are 32 patients diagnosed with PNH, and 25 of them show a polymorphonuclear neutrophils (PMN) PNH clone greater than 30%.

PNH etiopathogeny

Disease development is due to the following factors (2):

a) A somatic mutation of the PIG-A gene in a bone marrow stem cell. Due to this mutation, affected cells show deficiency or absence of glycosilphosphatidylinositol cell protein (GPI) [molecule essential for plasma membrane anchored proteins]. As a result, red blood cells are susceptible to lytic membrane attack complex.

b) Bone marrow failure contributes to the PNH clone proliferation with respect to normal cells.

PNH diagnosis and clinical significance

In PNH patients, three types of RBC or PMN can be detected: normal cells (Type I), cells which are partially deficient in GPI proteins (Type II), and cells completely lacking GPI proteins (Type III) (1).

Transfusions or hemolysis may alter the quatification of GPI-anchored protein deficient erythrocytes in PNH. As a result, the PMN clone quantification provides more information that the analysis of erythrocytes clone in PNH. Nowadays, flow cytometry is the method used in PNH diagnosis (2;3).

From a clinical point of view, the International Paroxysmal Nocturnal Haemoglobinuria Interest Group has established three PNH subcategories (2;3):

1. Classic PNH. Characterized by the evidence of florid intravascular hemolysis (macroscopic hemoglobinuria is frequent or persistent), with a PMN deficiency in GPI greater than 50%, and a predominance of red blood cells type III. Patients show no bone marrow related illness.

2. PNH related to other hemopathies, such as aplastic anemia or myelodysplastic syndrome. Rate of intravascular hemolysis is mild to


16 >

moderate (macroscopic hemoglobinuria is intermittent or absent). Percentage of GPI-deficient PMNs in these patients varies, but normally it is under 30%.

3. Subclinical PNH. There is no clinical or biochemical evidence of hemolysis, but small populations of GPI-deficient hematopoietic cells may be detected. PNH PMNs percentage analysed by flow cytometry is under 1%.

PNH spontaneous remission has been described in approximately 15-25% of the patients (1). This spontaneous remission is not related with illness severity or complications, as it even occurs in patients with high transfusion requirements who also suffered thrombotic events. Spontaneous remission usually occurs in 10 to 20 years after diagnosis. A possible explanation for this spontaneous remission could be that affected clones have a limited life span, such as somatic cells. Recovery may depend on the presence of normal cells capable of repopulate the bone marrow (4).

Classic PNH is characterized by triad of haemolytic anaemia, thrombophilia (affecting 12-40% of patients), and bone marrow failure (5). Median survival following diagnosis of PNH has been estimated as 10-15 years (1). Thrombosis is the main cause of morbidity, followed by infections and haemorrhage. Development of acute myeloid leukaemia is not frequent (less than 5% of the cases) (2;6).

When the quantity of PNH red blood cells type III is greater than 20%, patients usually show signs of intravascular haemolysis.

Presence of PNH granulocytes type II or III clones higher than 50% is associated to additional risk factors for thrombosis (7).

Also, PNH is characterized by the presence of anemia, asthenia, esophageal spasms, erectile dysfunction, recurrent abdominal pain, pulmonary hypertension, chronic renal failure, and worsening of health-related quality of life (1).

PNH treatment

Allogeneic haematopoietic stem cell transplantation is currently considered the only potentially curative option for PNH. Management of PNH is mainly supportive, a mean of controlling its clinical manifestations. Hence, treatment consists in red blood cells transfusions (RBC) in patients with serious haemolysis, corticosteroids treatment, and prophylactic anticoagulation.

Description of Eculizumab drug

Eculizumab (Soliris®) is a recombinant humanized monoclonal antibody. It belongs to the pharmacotherapeutic group of immunomodulators, ATC code: L04AA25. Eculizumab is an orphan drug of hospital clinical use.

At first, eculizumab treatment was researched in patients with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, and idiopathic membranous glomerulonephritis (6;8).

Mechanism of action Eculizumab specifically binds with high affinity complement factor (C5) protein,


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Inhibiting and thereby blocking its cleavage into active forms. As a result, it avoids the activation of C5b-9 terminal complement complex. Eculizumab blocks the red blood cells lysis in patients with PNH, in dose-dependent manner. It preserves the first components in the complex activation which are essential for the opsonization of microorganisms and to eliminate immune complexes (8).

EMA approval Eculizumab is indicated for the treatment of patients with PNH. Evidence of

eculizumab efficacy and safety in the treatment of PNH patients is limited to patients with history of transfusions of RBC (8).

Special warnings and precautions according to summary of product characteristics

Due to its mechanism of action, the use of eculizumab increases the risk of a Neisseria meningitidis infection. However, there is the risk of an illness caused by the less common serogroups (Y, W135, and X, specifically), though meningitis may be caused by any serogroup.

In order to reduce the risk of Neisseria meningitidis infection, all patients must be vaccinated at least two weeks before starting eculizumab treatment (9).

Table 1. Summary of characteristics of Eculizumab drug (9)

Presentation Concentrate for solution for infusion of 300 mg eculizumab single-use vial each containing 30 ml (10 mg/ml).

Dosage • Initial phase: 600 mg weekly for four weeks, followed by 900 mg in the fifth week. • Maintenance phase: 900 mg each 14 ± 2 days

Characteristics Intravenous infusion

Unit price (HPP +VAT)

4,628€ (10)

Justification

This report was commissioned by the SAS Management, in accordance with Resolution SC 0369/09, from August 7th, established for the Harmonised Criteria for Drug Use in all SAS centres.


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Main objectives

• Evaluate clinical efficacy of eculizumab in the treatment of patients with PNH in terms of increase of survival, reduction of the incidence of thromboembolic events, improvement of quality of life, diminishing packed red blood cells (PRBC's) transfusions, increase in hemoglobin levels, and diminishing haemolysis.

• Evaluate safety of eculizumab in patients with PNH.

• Provide an economic analysis of eculizumab in with PNH.

Secondary objectives

o Evaluate efficacy and safety of eculizumab treatment in patients with PNH de novo (without a history of transfusions).

o Evaluate efficacy and safety of eculizumab treatment in PNH patients under 18.

o Evaluate efficacy and safety of eculizumab treatment in patients with PNH receiving again eculizumab treatment after withdrawal.

o Evaluate efficacy and safety of eculizumab treatment in patients with PNH, during pregnancy.

Objectives


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Metodology

A multidisciplinary work panel of experts, coordinated and managed by the Andalusian Agency for Health Technology Assessment (AETSA), was constitued in order to elaborate an assessment report on eculizumab.

This work team was constitued by four methodologists, two technicians experts in drug documentation and information, two haematologists, a clinical pharmacologist, two clinical pharmacists, and four health-specialized economists.

External review was accomplished by a haematologist, a clinical pharmacist, an economist expert in pharmaceutical politics, and the Catalan Agency for Health Information Assessment and Quality (AATRM).

Systematic review of literature: efficacy and safety

To accomplish evidence-based response to efficacy and safety objectives it was performed an exhaustive research of the published literature in referential data sources until 12th February 2010.

Data base consulted for systematic review included the Cochrane Library, dat abase from the Center for Reviews and Dissemination (CRD), MEDLINE, EMBASE, ECRI and Hayes Inc. Besides, other information systems were consulted, such as Web of Knowledge and different web pages of drug and health technology assessment agencies (complete list in Appendix I).

In addition, the International Pharmaceutical Abstracts Database (IPA), AdisInsight (ADIS), Iowa Drug Information Service (IDIS) and Adverse Event Reporting System (AERS) from Food and Drug Administration (FDA) were consulted.

Appendix I also includes search strategies used in main data bases. In the rest of the data bases, searching was accomplished by means of keywords or using specific terms of each searching data base. No restriction by language was applied.

A manual cross-file searching was accomplished from bibliographical references in the selected papers.

Efficacy and safety searchings were accomplished separately by two AETSA and CADIME technicians specialized in drug documentation and information, in complementary databases, in order to find the maximum available information.

Selection criteria for systematic review of efficacy and safety

Inclusion criteria

• Population: PNH patients.

• Intervention: eculizumab treatment.

• Comparator: supportive care and/or placebo.

• Outcomes: survival, thrombotic events, quality of life, transfusions needs


22 >

(packed red blood cells), haemoglobin levels, haemolysis or adverse events.

• Procedure: meta-analysis, systematic reviews, clinical trials, EMA evaluation report, cohort studies, and before and after studies in at least 10 patients.

Exclusion criteria

• Studies performed with the following designs: narrative reviews, case series studies of less than 10 patients, clinical cases and editorials.

Systematic review of economic evaluation literature

In order to attain the economic goals, an exhaustive search of the published literature in referential data sources until 12th February 2010 was accomplished.

Consulted data bases for the review of the economic evaluation literature were NHS Economic Evaluation Database (NHS EED), EMBASE, MEDLINE and EuronHEED. In addition, other researchings were accomplished in various web pages of agencies for health technology assessment, and in the database of the evaluation group GENESIS of the Spanish Society of Hospital Pharmacy (SEFH) (complete list in Appendix I).

Appendix I details the search strategy of economic search in MEDLINE. Other searches were accomplished by means of keywords or using specific terms of each searching database.

Bibliographic search on economic aspects was undertaken by AETSA Documentation Service.

Selection criteria of the economic literature review

Inclusion criteria

• Population: PNH patients.

• Intervention: eculizumab treatment.

• Comparator: supportive care and/or placebo.

• Outcomes: economic information.

• Procedure: economic studies and healthcare technology assessment reports.

Selection, evaluation of quality, and synthesis of literature of efficacy, safety, and economics

• To elaborate a systematic review, papers were chosen by title and abstract. After a complete reading, all documents not meeting inclusion criteria were excluded.

• The evaluation of the quality of clinical trials, systematic reviews, and economic analysis were attained using specific evaluation scales from the Critical Appraisal Skills Programme (CASP), adapted by CASP Spain


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(CASPe) (11-13). Work team methodologists used a specific questionnaire to provide a critical evaluation on the quality of non-controlled intervention studies.

• Selection, critical reading, and qualitative synthesis of the evaluated studies were independently undertaken by two pairs of researchers (two methodologists and two clinical pharmacists). Discrepancies were solved in each pair by means of a discussion.

• Evaluation of safety was accomplished by the Andalusian Center of Pharmacovigilance (CAFV) and summarized by the methodologists.

• Two PNH clinical experts acted as consultants for the methodologists during the elaboration of this report.

• Economic evaluation and budget impact study in different scenarios were accomplished by the economists.

• Preliminary evaluation report was reviewed by all panel members.


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Results of efficacy and safety bibliographic search

In the bibliographic search of efficacy and safety on eculizumab treatment in patients with PNH, a total amount of 153 documents were found in different databases (70 in MEDLINE, 30 in EMBASE, 11 in the Cochrane Library, and 42 in the rest of databases). Figure 1 shows the flow diagram of the documents selection process during the systematic review. Complete text was obtained from 34 documents, seven of which met inclusion criteria.

Reasons for exclusion of the rest of studies are indicated in Appendix II.

Documents identified during search

(n = 153)

Documents after clearing duplicates

(n = 85)

Included documents (n = 7)

Papers excluded by title and abstract

(n = 51)

Excluded full papers

(n = 27)

Figure 1. Flowchart illustrating selection process of documents for the systematic review

Results


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Description of the documents included in the systematic review of efficacy and safety

The following documents were included: a systematic review (1), EMA’s eculizumab European Public Assessment Report (EPAR) (8), besides five clinical studies evaluating efficacy and safety of eculizumab treatment in patients with PNH: a phase II pilot study (14), a phase II extension study II (15), a randomised clinical trial (RCT) (TRIUMPH pivotal study) (16), and two interventional non-controlled studies [SHEPHERD study (17), and extension study including all patients (18)].

Eculizumab studies undertaken in patients with PNH (Figure 2):

Phase II studies:

o Descriptive pilot study (C02-001) with 11 patients, evaluated after 12 week treatment with eculizumab (14).

o Descriptive extension study of the previous study. Patients were evaluated 64 week after starting eculizumab treatment (E02-001) (15). Besides, an extension of the pilot study was undertaken during 104 weeks (X03-001). This study has not been published and its results are not included in the EMA EPAR.

Phase III studies:

o TRIUMPH: eculizumab RCT pivotal trial versus placebo (C04-001) (16). A 26-week study including 87 patients with PNH.

o SHEPHERD: uncontrolled study (C04-002) (17). This 52-week treatment study included 97 patients with PNH. Results of pre-treatment and after eculizumab treatment were analysed.

o Extension study: interventional non-controlled study (E05-001), including the 195 patients of the studies previously undertaken (phase II, TRIUMPH and SHEPHERD) (18). Ongoing study after the publication of the data.


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Figure 2. Flowchart showing eculizumab studies undertaken in patients with PNH

Hillmen et al. 2004 (14) Phase II, 12 week treatment, 11 patients

Hill et al. 2005 (15) Phase II, 52 week treatment, 11 patients

Phase II, 104 week treatment, 11 patients

Hillmen et al. 2006 (TRIUMPH) (16) Phase III, 26 week treatment, 87 patients

Brodsky et al. 2008 (SHEPHERD) (17) Phase III, 52 week treatment, 97 patients

Hillmen et al. 2007 (Extension study) (18) Phase III, 102 week treatment, 195 patients

Quality assessment of the studies

The TRIUMPH RCT (16) quality was low. Of 9 questions in the CASPe scale (11), 5 answers were negative (3 related to internal validity, and 2 related to external validity). Main endpoints in the RCT were surrogate endpoints.

Quality of the systematic review was good according to CASPe (12) scale. Of 8 questions of the scale, one answer related to external validity was negative.

Uncontrolled intervention studies [phase II study (14) and its extension (15), SHEPHERD study (17), and Hillmen et al. extension study (18)] are not valid designs to evaluate drug efficacy, given the possible biases associated to these type of designs. However, taking all this into account, these studies were accurate in the description of populations, patients baseline characteristics, inclusion criteria, and missing data during the follow-up.

RCT and systematic review quality evaluation results, according to CASPe scale, are indicated in Appendix III.


1. Baseline characteristics of patients included in the studies

Main baseline characteristics of patients included in the studies are described in the following table:

Table 2. Baseline characteristics of patients included in the pilot study (phase II), TRIUMPH and SHEPERD

FASE II (14) TRIUMPH (16) SHEPHERD(17) Patients

Eculizumab Eculizumab Placebo Eculizumab Main baseline characteristics n= 11 n= 43 n= 44 n= 97

pre-treatment 27% 21% 18% 43% thrombotic event incidence (%)

PRBC units-transfused the - 8

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previous 12 months (median, 18 17 (12-55) (0-66) range) LDH levels (median) (U/L) 3,111 2,051 2.032 2.234 (mean) (537-5.245) Percentage of PNH 97.0 95.3 96.0

(1.1-99.9)‡ †granulocytes(median, range) (47.8-99.8) (82.6-99.5)41 (mean) 35 (mean) 41 (meanna) Age (years) (median/mean, 48 (meanna)

(21-67) range) (20-85) (18-78) (18-78) Time from diagnosis (years) 4.3 9.2 4.9 8.7 (1.7-37.9) (median, range): (0.9- 29.8) (0.5-38.5) (0.1-31.4) Patients with history of aplasic &anemia or mielodisplasic 73% 18.7% 27.3% 32%syndrome (%)

55.8%* 45.5%*Patients with anticoagulant treatment (%) &55% 61%

# #49% 25 %

Patients with erythropoietin treatment (%) - 7% 0% -

† Data of 31 patients with baseline determinations (18) ‡ Data of 94 patients with baseline determinations (18) & Data published by Hillmen et al. 2007 (18) * Data from EMA’s eculizumab EPAR (8) # Data published by Hillmen et al. 2006 (16)


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In relation to patients baseline characteristics:

• Incidence of pre-treatment thrombotic events, in patients of the SHEPHERD study (17), doubled the one found in patients of TRIUMPH study (16).

• In the previous 12 months before eculizumab treatment, patients incluided in TRIUMPH RCT (16) had received more than double of PRBC units than patients included in the SHEPHERD study(17).

• In all studies (14;16;17), lactate dehydrogenase (LDH) baseline levels exceeded (almost nine times) the upper limit of normal (ULN).

• Patients age average in the different studies was similar.

TRIUMPH RCT (16) showed no differences among the baseline characteristics of both groups except duration of illness, aplasic anemia history, and patients treated with anticoagulants or with erythropoietin. Hillmen et al. (16) stated that these differences were not statistically significant, however, significance values of baseline characteristics differences were not indicated.

Major differences regarding inclusion criteria of patients in the studies

Major differences regarding inclusion criteria of patients in the studies were the number of PRBC transfused prior to eculizumab treatment and baseline platelets levels.

• Patients incluided in the SHEPHERD study (17) received less PRBC before starting treatment [≥1 PRBC units in the previous 24 months vs. ≥4 PRBC units in the previous 12 months before starting the phase II study (14) and the TRIUMPH RCT (16)].

• In the TRIUMPH RCT (16), patients included showed a baseline platelet count superior to 100,000/mm3 vs. superior to 30,000/mm3 in the SHEPHERD study (17).

2. Intervention in the studies

In all studies(14-18), during the induction phase, eculizumab was given to all patients with PNH, at one 600 mg dose weekly for four weeks followed by a 900 mg dose in the fifth week. Then, in the maintenance phase, 900 mg every two weeks.

In two patients of the phase II extension study (15), a patient of the TRIUMPH RCT (16), and eight patients of the SHEPHERD study (17), it was necessary to modify the dosage regime during the maintenance phase, due to an increment in the haemolysis in the last two days of the interval dosing. These patients received eculizumab every 12 days. Haemolysis was reduced in the two patients involved in the extension study (15) and six of the SHEPHERD patients whose dosage regime was adjusted (17).


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3. Main results of efficacy and safety

Results from the systematic review are displayed following the clinical relevance order given by the evaluated endpoints (survival, thrombotic events, quality of life, PRBC transfusions requirements, and haemoglobin and haemolysis levels).

Survival

No studies evaluating survival in PNH patients under eculizumab treatment were reported. The extension study including 195 patients had the longest monitoring period (102 weeks ) (18).

Incidence of thrombotic events

The only study which evaluated the incidence of thrombotic events in patients with PNH under eculizumab treatment was the extension study by Hillmen et al. (1;18). This study included the patients participating in the pilot, TRIUMPH, and SHEPHERD studies.

Main endpoint of the extension study was the rate of major adverse vascular events (MAVE) or thrombotic events. Pre-treatment MAVEs were evaluated through a retrospective analysis of the patients’ medical history. Of all pre-treatment MAVEs considered in the study, only 73% of them had diagnostic confirmation.

MAVEs included thrombophlebitis, deep vein thrombosis, pulmonary embolus, cerebrovascular accident, amputation, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis, mesenteric vein thrombosis, portal vein thrombosis, gangrene, acute peripheral vascular occlusion, sudden death, and other events.

Incidence of thrombotic events in patients with PNH decreased from 7.37 events/100 patients-year (124 events) before eculizumab treatment to 1.07 events/100 patients-year (3 events) after treatment (p< 0.001).

Within the subgroup of patients who received antithrombotic therapy before the study, thrombotic events rate decreased from 10.61 events/100 patients-year before eculizumab treatment to 0.62 events/100 patients- year after treatment (p< 0.001).

In the study, similar time periods before eculizumab were also compared. When considering the same time period of pre-treatment and post-treatment with eculizumab, the number of thrombotic events was 39 and 3, respectively (p< 0.001).

The paper of the extension study (18) also showed thrombotic events results after 26 weeks in the TRIUMPH RCT. One patient from the placebo group developed a thrombotic event vs. 0 in the eculizumab group. The proportion of anticoagulated patients in the RCT was of 45.5% in the placebo group vs. 55.8% in the eculizumab group, according to the EPAR (8). Nevertheless, according to Hillmen et al. paper (16), proportion of anticoagulated patients in the RCT was 25% in the placebo group vs. 49% in the eculizumab group.


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Quality of life

Quality of life was evaluated as secondary endpoint in the pilot study (14) and its extension (15), TRIUMPH (16) and SHEPHERD (1;17). It was assessed by means of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Appendices IV and V show both scales and a brief description of each.

Baseline score of patients quality of life obtained in both scales was not indicated in the TRIUMPH or SHEPHERD studies. Baseline score obtained in the EORTC QLQ-C30 scale was only indicated in the phase II study.

In the SHEPHERD study, patients’ quality of life, measured in both scales before and after eculizumab treatment, showed a major improvement over patients who received eculizumab in the TRIUMPH RCT. It is necessary to bear in mind that patients in the RCT received a transfusion prior to quality of life analysis, while in the SHEPHERD study, they did not received it.

FACIT-Fatigue scale TRIUMPH RCT (16) showed that in patients treated with eculizumab, the mean

score in the FACIT-Fatigue scale increased 6.4 ± 1.2 points, while in patients who received placebo, median score decreased 4.0 ± 1.7 points (p< 0.001). 53.7% of eculizumab group patients showed a change in the FACIT-Fatigue scale ≥ 4 points (minimal clinically important difference) with respect to a 20.5% of patients in the placebo group (p=0.0028) (see Table 7) (8).

In the SHEPHERD study (17), median score of FACIT-Fatigue scale in PNH patients increased 12.2 points (p<0.001).

EORTC QLQ-C30 scale At the beginning of the pilot study, median score of overall health status in the

eleven patients who received eculizumab was of 56.1. It was observed a change of 13.7 points after 12 weeks of treatment (p=0.02), and a change of 13.8 points after 64 weeks with eculizumab (p<0.009) (14;15) (see Tables 5 and 6).

En el RCT TRIUMPH (16), there were statistically significant differences among both treatment groups in all EORTC QLQ-C30 scale items, except those of nausea and vomits, financial difficulties, constipation, and diarrhea. In the SHEPHERD study (17) there were also observed statistically significant differences before and after eculizumab treatment, in the same items of the EORTC QLQ-C30 scale (see Tables 7 and 8).

Transfusions of Packed Red Blood Cells

The number of PRBC units transfused to each patient was evaluated as main efficacy endpoint in TRIUMPH (16) and SHEPHERD (17) studies. Besides, the same endpoint was evaluated in the phase II study en (14) and its extension (15). In the


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TRIUMPH RCT (16) it was evaluated the number of PRBC units transfused per patient was evaluated contrasting the eculizumab group vs. the placebo group. In both phase II studies (14;15), and in the SHEPHERD study (17), the number of PRBC transfused per patient, was evaluated before and after eculizumab treatment. Also, both TRIUMPH RCT and SHEPHERD study evaluated the proportion of patients achieving transfusion independence during eculizumab treatment (1;16;17).

In the TRIUMPH RCT (16), the median of PRBC units transfused was of 10 (range 2-21) in the placebo group versus 0 (range 0-16) in the eculizumab group (p< 0.001). Likewise, in the SHEPHERD study (17), the median of transfused PRBC units in the 12 months pre-treatment was of 8 versus 0 (p< 0.001) in the following 12 months.

Patients of TRIUMPH RCT were randomized into three groups, according to the number of PRBC units who received during the 12 months prior to enrolling in the study (4-14, 15-25 and > 25 PRBC units). When groups results are individually analysed, the difference in the median of required PRBC units was of 6 (p< 0.005), 8 (p< 0.005), and 15 (p< 0.005), respectively (8) (see Table 7).

In the SHEPHERD study (17), patients were stratified into four groups, according to baseline level of LDH: 537-1,379; 1,380-2,050; 2,051-2,866; and 2,867-5,245 U/L. In patients with a baseline level of LDH among 537 and 1,379 U/L, the reduction of transfused PRBC units before and after eculizumab treatment was not statistically significant. However, patients with baseline levels of LDH superior to 1,380 U/L, reductions of transfused PRBC units before and after eculizumab treatment were statistically significant.

Differences observed before and after the median in each of the four groups were of 8 PRBC units (p= 0.143), 6.5 PRBC units (p= 0.033), 9 PRBC units (p<0.001), and 6.5 PRBC units (p=0.006), respectively (see Table 8).

On the other hand, phase II study (14) and its extension study(15), showed that the median of transfused PRBC units patient/months decreased from 1.8 to 0 (p= 0.003) and to 0.3, after 12 weeks and 64 weeks of eculizumab treatment, respectively (see Tables 5 and 6).

51% of the patients who received eculizumab, according to TRIUMPH RCT, required no transfusions during the 26 week-treatment; while all patients in the placebo group required transfusions (p<0.001) (16). Same percentage of patients in the SHEPHERD study (51%) achieve transfusion independence during the 52-week treatment with eculizumab (p =0.001) (17).

Haemoglobin levels

Percentage of patients with stable haemoglobin levels was only evaluated in the TRIUMPH RCT (primary efficacy endpoint) (1;16). 48.8% of patients treated with eculizumab showed stable haemoglobin levels vs. 0% of patients in the placebo group (p<0.001) (16).

When analysing stratification, depending on the number of PRBC received during the 12 months prior to the study (4-14, 15-25 and > 25 PRBC units), it was observed that eculizumab group patients showed stable haemoglobin levels in 80% (p<0.001), 29.4% (p=0.02), and 36.4% (p=0.09) of the cases, respectively (8).


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Haemolysis

Haemolysis was evaluated through LDH level, area under curve (AUC) of LDH, and percentage of PNH type III erythrocyte population (1).

In the TRIUMPH RCT (16), after 26 weeks of treatment, LDH levels were reduced from 2,199.7 ± 157.7 to 327.3 ± 67.6 U/L in patients who were treated with eculizumab. In patients who received placebo, LDH levels remained high, ranging from 2,258.0 ± 154.8 to 2,418.9 ± 140.3 U/L (p< 0.001).

Both in TRIUMPH RCT (16) and SHEPHERD study (17), in patients under eculizumab treatment, LDH levels were significantly reduced towards normal range (103-223 U/L) after the first month of treatment, and they were closer to normal range during monitoring (p< 0.001).

In the TRIUMPH RCT (16), patients of placebo group showed a constant percentage of PNH type III erythrocyte population (35.7 ± 2.8% before starting the RCT and 35.5 ± 2.8% after 26 weeks). Reduction of intravascular haemolysis within eculizumab patients generated an increase of PNH type III erythrocyte population (from 28.1% ± 2.0% to 56.9% ± 3.6%) (p<0.001). Similarly, in the SHERPHED study (17), there was an increment of PNH type III erythrocyte population (from 38.7 ±2.17% to 55.4 ± 2.85%) after 52 weeks of eculizumab treatment.

Adverse events

Eculizumab is a new treatment for PNH of recent commercialization, so there is no evidence of long-term safety.

Clinical trials data

Safety was evaluated in the phase II pilot study (14), in the extension study of the phase II study (15), in the TRIUMPH RCT (16), and in the SHEPHERD uncontrolled intervention study (17).

Meningococcal infection was the most serious adverse event (AE) observed related to eculizumab treatment. Out of 195 patients with PNH and other 716 patients with other pathologies, all treated with eculizumab, there were 3 cases of meningitis (one of them in a non-vaccinated patient without PNH, and two cases in vaccinated PNH patients). Therefore, 0.3% of patients under eculizumab treatment developed meningococcal infection (8).

TRIUMPH RCT (16), reported no significant differences in the frequency of adverse events among patients treated with eculizumab and the placebo group. In the SHEPHERD study (17), the percentage of patients with serious adverse events (SAES) during the 52 weeks of treatment was 7.2%.

91.8% of patients included in the SHEPHERD study suffered from one or more infections (one infection: 15.5% of patients; two infections: 33% of patients; three or more infections: 43.3% of patients). 74.7% of infections were mild, 24.2% moderate, and 1.1%


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severe. 29.9% of patients under eculizumab treatment showed an upper respiratory tract infection and the 13.4 % an urinary tract infection (17).

Most frequent AE are described in the following table:

Tabla 3. Adverse events most frequently observed in the studies

TRIUMPH (16) SHEPHERD (17) Datos combinados TRIUMPH/SHEPHERD (8)

26 weeks 52 weeks 26 weeks Most frequent AE (>10% in some groups)

Eculizumab

n= 43

Placebo

n= 44

Eculizumab

n= 97

Eculizumab

n=140 Cephalea

44% 27% 53% 50%

Nasopharyngitis 23% 18% 32% 25%

Upper respiratory tract infection 14% 23% 30% -

Nausea 16% 11% 21% 17%

Pyrexia - 5% 20% 14%

Back pain 19% 9% 15% -

Myalgia - - 10% 8%

Fatigue 12% 2% - 8%

One patient of each treatment groups in the TRIUMPH RCT (16) showed low antibody levels against eculizumab. The antibodies of the patient who received eculizumab did not affect complement inhibition. In the SHEPHERD study (17), 2.1% of patients developed neutralising antibodies after 52 weeks of treatment with eculizumab.

Safety data from secondary sources

In the FDA Adverse Event Reporting System (19) (AERS) database, 31 notifications have been found containing a total amount of 91 adverse events associated with eculizumab treatment. 18.7% of these events is associated to infusion-related reactions and general disorders, and 12.1%, with infections.

The EMA (8;20) established a risk management plan which specified activities related to pharmacovigilance and risk minimization, regarding the following safety aspects:

• Meningococcal infection (identified risk).

• General infections (potential risk).

• Serious haemolysis after treatment withdrawal (potential risk).


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• Cephalea (identified risk).

• Infusion reactions (potential risk).

• Immunogenicity (potential risk).

• Hematologic Malignancies (potential risk).

• Pregnancy and lactation (no information available).

• Experience in children (no information available).

• Renal impairment (no information available).

• Hepatic impairment (no information available).

Other clinical situations

Efficacy and safety of eculizumab treatment in patients with PNH de novo

No studies were found that accomplished the inclusion criteria of the systematic review, and which also evaluated efficacy and safety of eculizumab treatment in patients de novo.

In the SHEPHERD study (17) there were included patients who did not receive RBC transfusions in the 12 months prior to beginning of treatment. Notwithstanding, they were no patients de novo, as they had received at least one PRBC transfusion during the 24 months prior to beginning of study.

Efficacy and safety of eculizumab treatment in PNH patients under 18

No studies were found that evaluated efficacy and safety of eculizumab treatment in PNH patients aged ≤ 18 years.

Reintroduction of eculizumab treatment

No studies were found that evaluated efficacy and safety of reintroduction of eculizumab, after withdrawal from treatment, in patients with PNH.

Eficacia y seguridad del tratamiento con eculizumab durante el embarazo

No se localizaron estudios que cumplieran los criterios de inclusión de la revisión sistemática y que evaluaran la eficacia y seguridad del tratamiento con eculizumab durante el embarazo, en pacientes con HPN.

Efficacy and safety of eculizumab treatment during pregnancy

No studies were found that accomplished the inclusion criteria of the systematic review and that evaluated efficacy and safety of eculizumab treatment during pregnancy in patients with HPN.


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Table 4. Summary of studies results

Study Type of Study n Intervention

Group Control Group Primary endpoints Secondary endpoints

Primary endpoints analysis

Time of treatment

PHASE II descriptive 11 Eculizumab - ITT 12 weeks Phase II extension descriptive 11 Eculizumab - ITT 12 + 52

weeks Phase II extension descriptive 11 Eculizumab -

PRBC units transfused/ patient/month Hb levels LDH levels Hemoglobinuria (days/patient/month) Quality of life ITT 104 weeks

TRIUMPH RCT and DB 87 Eculizumab Placebo % of patients with stable Hb levels

PRBC units transfused/patient

% of patients avoiding transfusions AUC and LDH levels Quality of life

ITT 26 weeks

SHEPHERD descriptive 97 Eculizumab - % of patients with serious adverse events PRBC units transfused/patient

% of patients avoiding transfusions Quality of life

ITT 52 weeks

EXTENSION descriptive 195 Eculizumab - Thrombotic events rate (nº per 100 patients-year) ITT 102 weeks


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Table 5a. Phase II study, Hillmen et al. 2004 (14). Most relevant aspects of Phase II study

SAMPLE SIZE 11 patients with PNH. PATIENTS’ LOSSES 0 patients.

DESIGN Phase II, descriptive pilot study, accomplished in two hospitals in the United Kingdom.

TREATMENT Eculizumab 600 mg i.v. weekly (4 dose), followed by a 900 mg dose in the 5th week. Then, 900 mg every 2 weeks.

OTHER DATA OF INTEREST REGARDING TREATMENT AND STUDY

concomitant immunosuppressant therapy (f.e. cyclosporine), warfarin, and iron supplements were allowed. 2 of 11 patients had a history of thrombosis. 6 of 11 patients were treated with warfarin before and during treatment. 8 of 11 patients had a history of aplastic anemia.

INCLUSION CRITERIA

Patients ≥ 18 years. PNH diagnosed using flow cytometric analysis, at least 6 months before beginning of study. ≥ 4 transfusions in the previous12 months before beginning of study. Negative throat culture for Neisseria meningitidis and N. gonorrhoeae.

TYPE OF ANALYSIS ITT, Alexion Pharmaceuticals reviewed the manuscript and provided feedback.

Table 5b. Phase II study, Hillmen et al. 2004 (14). Measured variables

ENDPOINT EVALUATED IN THE STUDY

Before eculizumab treatment (n= 11)

After 12 weeks of eculizumab treatment (n= 11) P

PRBC units/patient/month (mean)

2.1 0.6 0.003

PRBC units/patient/ month (median) 1.8 0.0 0.003

LDH (median ± DE) IU/L 3,111 ± 598 594 ± 32 0.002

Incidence of hemoglobinuria (mean) (days/patient/ month) 2.9 0.12 0.001

Quality of life EORTC QLQ-C30 Global health Physical status Emotional status Cognitive status Fatigue Dyspnea Insomnia

Median baseline score 56.1 70.9 70.5 77.3 47.5 39.4 30.3

Change in the scores

13.7 13.0 12,7 11.8 -15.3 -12.4 -10.8

0.02 <0.001 <0.001 0.002

<0.001 0.002 0.049

LDH (normal range): 150-480 U/L


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Table 6a. Extension study of phase II study, Hill et al. 2005 (15). Most relevant aspects of Phase II study

SAMPLE SIZE 11 patients with PNH.

PATIENTS’ LOSSES 0 patients.

DESIGN Descriptive study.

TREATMENT Eculizumab maintenance regimen during 52 weeks, 900mg every two weeks.

TYPE OF ANALYSIS ITT, Alexion Pharmaceuticals reviewed the manuscript and provided feedback.

Table 6b. Extension study of phase II study, Hill et al. 2005 (15). Variables


Before eculizumab treatment ( n= 11)

After 64 weeks of eculizumab treatment

(n= 11) p

PRBC UNITS /patient/month (mean) 2.1 0.5 ---

PRBC UNITS /patient/month (median) 1.8 0.3 0.001

LDH (mean ± SD) IU/L 3,111 ± 598 622.4 ± 41.1 0.002 Haemoglobin (g/dL) 10.0 ± 0.4 10.4 ± 0.4 NS Platelets x 109/L 183.0 ± 35.3 180.8 ± 35.8 NS PNH Erythrocyte type III (%) 36.7 ± 5.9 58.4 ± 8.5 0.005 Hemoglobinuria incidence (mean) (days/patient/month) 2.9 0.2 0.001

Quality of life EORTC QLQ-C30

Global health Physical status Emotional status Psychological status Cognitive status Fatigue Dyspnea Insomnia Pain Constipation

Median baseline score

56.1 70.9 70.5 66.7 77.3 47.5 39.4 30.3 21.2 3.0

Change in the scores

13.8 14.3 12.5 14.5 10.3 -17.8 -16.6 -8.2 -8.2 4.1

0.009 <0.001 <0.001 0.003 0.001

<0,001 <0.001 0.031 0.023

<0.001 Haptoglobine, bilirubin, and reticulocytes levels did not change significantly when patients were treated with eculizumab.

Normal range for a platelet count: 150-400 x 109/L.


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Table 7a. TRIUMPH randomised clinical trial (8;16). Most relevant aspects of study


PATIENTS’ LOSSES

85 patients completed treatment period in the study. 2 patients of eculizumab group did not complete the RTC, one of them due to problems in accesing the study centre, the other due patient due to pregnancy. 10 patients of placebo group discontinued infusions. However, monitoring continued until study completion.

DESIGN

Phase III, RCT, DB and multicenter (34 centres in USA, Canada, Europe, and Australia). Stratified randomization according to the number of PRBC units required in the previous 12 months before study began. Three groups:

between 4 and 14 of PRBC units. between 15 and 25 of PRBC units. > of 25 of PRBC units.

2 weeks of population screening + 3 months of monotorization + 26 weeks of treatment.

Active group: Eculizumab 600 mg i.v. weekly (4 doses), followed by 1 dose of 900mg in the 5th week; then 900mg every 2 weeks.

TREATMENT

Control group: Placebo i.v. weekly (5 doses), then every 2 weeks.

OTHER INTEREST DATA IN RELATION TO TREATMENT

concomitant therapy allowed: erythropoietin, immunosuppressants, anticoagulants, iron supplements, and folic acid. Concomitant theraphy, steady doses, from 26 weeks before starting treatment and during treatment.

INCLUSION CRITERIA

Patients aged ≥ 18. Erythrocytes PNH type III percentage ≥ 10%, confirmed by flow cytometry. ≥ 4 transfusions in the 12 months prior to beginning of study, and one transfusion at least during the 13-week monitoring period. Platelets count > 100.000/mm3. LDH ≥ 1,5 x ULN. Neutrophils count ≤ 500/μL.

EXCLUSION CRITERIA

Patients with hereditary complement deficiency, active bacterial infection or meningococcal disease history; patients who received an allogeneic hematopoietic cell transplantation.

TYPE OF ANALYSIS ITT analysis was only accomplished in major endpoints. Data were analyzed by Alexion laboratory.


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Table 7b. TRIUMPH randomised clinical trial (8;16). Variables


Eculizumab n= 43

Placebo n= 44

ARR (IC 95%) p NNT

Results of major endpoints Pacientes en los que se estabilizan los niveles de Hb

48,8 % 0,0% 48,8 % (33,9-63,8%) < 0,001 3

(2-3)

Patients who stabilized their Hb levels (%), towards the end of the study. Stratified data according to the number of transfusion received in the 12 months prior to study

4 -14 PRBC units (ne=15, np=15) 80.0% 0.0% 80.0%

(59.8-100.2%) < 0.001 2 (1-2)

15 and 25 PRBC units (ne=17, np=18)

29.4% 0.0% 29.4% (7.8-51.1%) 0.02 4

(2-13)

> 25 PRBC units (ne=11, np=11) 36.4% 0.0% 36.4%

(7.9-64.8%) 0,09 3 (2-13)

PRBC units transfused/patient (median, range)

0 (0-16) 10 (2-21) - < 0.001 -

PRBC units transfused per patient. Stratified data according to the number of transfusion received in the 12 months prior to study

4 -14 PRBC units (ne=15, np=15) 0 (0-4) 6 (2-

12) - < 0.001 -

15-25 PRBC units (ne=17, np=18) 2 (0-15) 10 (2-

21) - < 0.001 -

> 25 PRBC units (ne=11, np=11) 3 (0-16) 18

(10-20) - < 0.001 -

Secondary endpoints results Patients with transfusion independence 51.0% 0% 51.0%

(36.1-65.9%) < 0.001 2 (2-3)

LDH level towards the end of study (median, U/L)

239 2,167 - < 0.001 -

Mean change in quality of life (FACIT-Fatigue) 6.4 ± 1.2 - 4.0 ± 1.7 - < 0.001 -

Patients with changes in quality of life FACIT-Fatigue scale ≥ 4 (minimal relevant difference)

53.7% 20.5% 33.1% (13.3-53.0%) 0.002 4

(2-8)

Quality of life with EORTC QLQ-C30 Global health status Role status Social skills Cognitive status Physical status Emotional status Fatigue Pain Nausea and vomits Dyspnea Lack of appetite Insomnia Economic difficulties Constipation Diarrhea

10.9 17.9 16.7 7.9 9.4 7.5

-16.9 -12.3 -0.4 -7.9

-10.3 -7.9

-10.3 -6.3 4.8

-8.5 -6.9 2.0 -6.1 -3.5 -3.7 10.0 5.3 2.8 8.9 3.3 4.9 0.0 0.0 5.7

- - - - - - - - - - - - - - -

<0.001 <0.001 0.003 0.002

<0.001 0.008

<0.001 0.002 0.06

<0.001 <0.001

0.01 0.19 0.20 0.15

- - - - - - - - - - - - - - -

Safety results

Serious adverse events 9.3 % 20.5 % 11.2% (-3.6-25.9%) - 9

(4-28)


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Table 8a. SHEPHERD study (17). Most relevant aspects of study

POPULATION 97 patients with PNH.

PATIENTS’ LOSSES

96 patients completed the 52-week study.

One patient did not finish study period due to an AE not related to the study drug.

DESIGN Phase III, multicenter descriptive study (USA, Canada, Europe, and Australia).

2 weeks of screening + 52 weeks of treatment.

TREATMENT Eculizumab 600mg i.v. weekly (4 doses), followed by one 900mg dose in the 5th week; then 900mg every 2 weeks.

INCLUSION CRITERIA

Patients ≥ 18 years. Percentage of RBC type III ≥ 10% confirmed by flow cytometry. ≥1 transfusion in the previous 24 months prior to study. Platelets count > 30 x 109/L. LDH ≥ 1.5 x ULN.

EXCLUSION CRITERIA

Neutrophils count ≤ 500/μL (= 0.5 x 109/L). Patients with hereditary complement deficiency, active bacterial infection or meningococcal disease history; patients who received an allogeneic hematopoietic cell transplantation.

TYPE OF ANALYSIS ITT

Table 8b. SHEPHERD study (17). Variables


Before eculizumab treatment

n= 97


n= 97 p

Safety results % patients with serious adverse events * - 7.2

% patients experiencing one or more infections ** - 91.8

% patients developing antibodies - 2.1 Efficacy results

PNH erythrocytes type III (%) (median) 33.5 55.7 < 0.001

PNH erythrocytes type III (%) (mean ± SD) 38.7 ± 2.17 55.4 ± 2.85

% patients who avoided transfusion - 51 < 0.001

Stratification results. in four groups. according to baseline LDH value. in relation to the percentage of patients achieving transfusions independence (%).

LDH between 537-1.379 U/L (n=25) - 60 < 0.001

LDH between 1.380-2.050 U/L (n=24) - 50 0.021

LDH between 2.051-2.866 U/L (n=24) - 50 < 0.001

LDH between 2.867- 5.245 U/L (n=24) - 42 0.021

Number of transfused PRBC /patient [median (mean ± SD)]

8.0 (12.3 ± 1.25) previous 12 months

0.0 (5.9 ± 1.06) following 12 months < 0.001

Stratification results. in four groups. according to baseline LDH values. in relation to the number of


42 >

Table 8b. SHEPHERD study (17). Variables



n= 97


n= 97 p

transfused PRBC/ patient [median (mean ± SD)]. LDH between 537-1.379 U/L (n=25) 8.0 (11.3 ± 2.21) 0.0 (7.6 ± 2.41) 0.143

LDH between 1.380-2.050 U/L (n=24) 7.5 (11.3 ± 2.38) 1.0 (7.9 ± 2.77) 0.033

LDH between 2.051-2.866 U/L (n=24) 9.5 (14.3 ± 3.15) 0.5 (2.6 ± 0.91) < 0.001

LDH between 2.867-5.245 U/L (n=24) 8.5 (12.3 ± 2.27) 2.0 (5.4 ± 1.82) 0.006

Quality of life change (FACIT-Fatigue) [mean ± SD] (n=95) - 12.2 ± 1.1 <0.001

Quality of life change (FACIT-Fatigue) [median] (n=95) - 10.0

Stratification results. in four groups. according to baseline LDH values. in relation to quality of life change (FACIT-Fatigue) [median]

LDH entre 537-1.379 U/L (n=23) - 8.0 LDH entre 1.380-2.050 U/L (n=24) - 9.0 LDH entre 2.051-2.866 U/L (n=24) - 10.5 LDH entre 2.867- 5.245 U/L (n=24) - 15.5

Quality of life EORTC QLQ-C30 (change mean after 52 weeks of treatment ± SD).

Global health Role status Social skills Cognitive status Physical status Emotional status Fatigue Pain Nausea and vomits Dyspnea Lack of appetite Insomnia Economic difficulties Constipation

- - - - - - - - - - - - - -

19.7 (2.05) 20.4 (2.67) 17.4 (2.84) 8.6 (2.26)

14.8 (1.63) 15.6 (2.26) 27.5 (2.32) 8.1 (2.61) 2.5 (1.54) 7.9 (2.11)

11.6 (2.77) 1.8 (1.96) 0.7 (2.78) 0.4 (2.03)

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 <0.001 0.002

< 0.001 < 0.001 < 0.001 0.768

0.4 (2.03) * Serious adverse events were: pyrexia (2.1%). headache (1%). abdominal distension (1%). viral infection (1%). anxiety (1%). and renal failure (1%). **74.7% of infections were of mild intensity. and 24.2% of moderate intensity.

Table 9a. Extension study by Hillmen et al. 2007 (18). Most relevant aspects of study


DESIGN Intervention descriptive multicenter before/after study.

TREATMENT

Patients previously treated with eculizumab, continued receiving 900mg eculizumab every 2 weeks, during 102 weeks. Patients formely included in the placebo group in the TRIUMPH study received eculizumab 600 mg i.v. weekly (4 doses), followed by 1 dose of 900mg in the 5th week; then 900mg every 2 weeks.

OTHER DATA OF INTEREST REGARDING TREATMENT

concomitant immunosuppressant therapy, anticoagulants, and iron supplements were allowed. Doses could be modified by clinician.

INCLUSION CRITERIA

• Patients who completed all previous studies (Phase II and its extensions, TRIUMPH, and SHEPHERD).

• Patients included in the TRIUMPH study who withdraw eculizumab therapy before last study-stage due to lack of efficacy or exacerbation of PNH symptoms, and who completed all monthly safety and efficacy evaluations.

EXCLUSION CRITERIA

• Patients who finished early extension studies of Phase II study, SHEPHERD, and TRIUMPH due to adverse events.

ANALYSIS TYPE ITT


< 43

Tablee 9b. Extension study by Hillmen et al. 2007 (18). Variables

ENDPOINTS EVALUATED IN THE STUDY


n= 195

After eculizumab treatment

n= 195 p

Thrombotic events (n) 124 3

Thrombotic events rate (nº per 100 patients-year) * 7.37 1.07 < 0.001

Thrombotic events (n) comparing same period of time before and after eculizumab treatment

39 3 < 0.001

Thrombotic events in patients who received antithrombotic therapy (n=103)

40 1 < 0.001

Thrombotic events rate in patients who received antithrombotic therapy (nº per 100 patients-year)

10.61 0.62 < 0.001


< 45

Economic evaluation results

This section includes:

A. A review of the literature on economic aspects.

B. A critical analysis on the information provided by the industry.

C. An economic analysis de novo.

A. Review of the literature on economic aspects

Four documents which included economic information regarding eculizumab treatment for patients with PNH were taken into account. One of them was excluded from consideration, as it was a letter to the director. The other three studies included were: two reports of health technologies assessment (1;21) and a report evaluation of medicinal products by the Pharmacotherapeutic Guide of Andalusian Hospitals (22). The first two are related to the United Kingdom Health System and the third is related to the SSPA.

Evaluation results of the quality of the economic reports, according to CASPe scale are indicated in Appendix III.

Description

The report by The West Midlands Health Technology Assessment Collaboration (WMHTAC) reviewed evidence about natural history, prevalence, and prognosis of PNH, as well as clinical efficacy and cost-efficacy of eculizumab treatment (1). In addition, three economic analysis were undertaken with the aim of calculating the incremental cost-effectiveness ratio.

The report accomplished by All Wales Medicines Strategy Group presented a critical review and analysis on the evaluations of the report by the WMHTAG, and the comments on it submitted by the company (21). For this reason, a conjoint analysis of both reports have been attained.

The accomplished analyses are presented below:

1. Cost per life year gained with eculizumab treatment

European cohort studies which evaluated PNH natural history showed that patients with more than 25 years of disease, worsen their life expectancy in 4.5 and 10.2 years in relation to general population. Though there is no evidence of drug impact in terms of mortality, authors considered that survival after eculizumab treatment equaled survival of general population, due to the reduction of thrombotic events rate achieved with treatment. In this case, over a 25 year time horizon, the cost of eculizumab per life year gained was estimated to be between £0.6 million and £1 million, with a discount rate of 3.5%. The same analysis was done taking into account the saving from the use of eculizumab. As there are no published estimates for the costs, authors assumed it to be between £1,000 and £100,000 per patient. Treatment with eculizumab would save


46 >

between 50% and 90% of the cost of life support treatment. With these assumptions, incremental cost per life year gained ranged from £0.5 million to £1.4 million (1;21).

The company submission states that incremental cost of £1.4 million uses an excessively low estimate of life year gained with treatment (4.5 years). The statement was not taken into account and authors pointed out that in any case, even in more in more favourable circumstances for this drug, cost-efficacy ratios were still quite high (lowest ratio was of 0.6 millions) (1;21).

2. Cost per year gained for averting thrombotic events thrombotic after treatment with eculizumab

Cost per life year gained was estimated as result of thrombotic events averted due to eculizumab treatment. Costs of thrombotic events were not considered due to lack of data. A time horizon of 10-15 years (based on reported median survival data of media en patients with PNH) was used together with a discount rate of 3.5%. Thrombotic events before/after antes- eculizumab treatment were 7.37-1.07 events/100 patients- year. Mortality rates of 52% for patients with thrombotic events, and 15% for patients without thrombosis were used. In light of the aforementioned premises, incremental cost-efficacy was ranged from £1.2 million to £1.4 million per life year gained, for a estimated median survival of 10-15 years, respectively (1;21).

It was included a sensitivity analysis varying rate of thrombotic events of 4.22 per 100 patient-years for patients without use of eculizumab. It was considered that after treatment, thrombotic events rate diminished to 0.61 per 100 person-years. Incremental cost-efficacy in this case was estimated as £2.8 million £3.2 million per life year gained, assuming a survival period of 15 and 10 years, respectively (1;21).

3. Cost of haemoglobin and LDH levels stabilization with eculizumab treatment

This analysis calculated cost-efficacy ratios based on TRIUMPH RCT efficacy data. The first year of treatment was estimated in £252,000, so the cost of the 26 week-RCT was of £126,000. Incremental cost-efficacy ratio estimated to stabilize haemoglobin levels with eculizumab treatment was of £257,142 and the cost of stabilizing LDH levels was of £340,541 (1;21).

When it was considered the cost of lowering LDH levels to a level which provided clinical benefit to patient, incremental cost- effectiveness ratio decreased to £132,492 (1;21).

Laboratory company claimed that those sums could be revised downwards if costs of clinical practice savings were included, savings resulting from clinical benefit obtained with the use of eculizumab. The response was that those costs are unknown (1;21).

In the same way it was accomplished a critical review of budget impact submitted by the company. They considered that in order to establish net budget impact of drug financing, saving costs for health system due to eculizumab clinical benefits must be contemplated. Expenditure of normal clinical practice resulting of PNH treatment includes varied interventions (from PRBC transfusions to analgesics or anticoagulants) and the study did not assess estimation and valuation of those costs. This was the major limitation of the analysis. As alternative, a saving range between £1,000 and £200,000 was estimated, but it was too broad and unrealistic, as there is a two-hundred times


< 47

difference in pounds among the two extremes (1;21).

Authors concluded that:

• Economic evidence is too limited at present, and

• One limitation of the report is that cost- effectiveness was calculated by inadequate result measures and incomplete cost estimations.

Finally, eculizumab evaluation report accomplished for the Pharmacotherapeutic Guide of Andalusian Hospitals (22) estimated the incremental cost- efficacy for the major endpoint in the TRIUMPH RCT. The cost for a patient to be transfusion-independent during a year was of 698,900€. This estimation took into account the saving due to reduction of the amount of PRBC units required. Cost of PRBC unit used in the estimation was of 750€. This is a much superior cost that the one provided by the BOJA 210, 27th Octubre 2005, which stipulates public prices for the health care services provided by centers dependant of the Andalusian Public Health System. The autonomous agency establishes a price of 68.09 €.

This report also estimated the incremental cost of eculizumab treatment con eculizumab regarding allogeneic haematopoietic stem cell transplantation. Starting from a cost estimation of this transplantation provided by Alexion Pharma, incremental cost was of 316,141.22€. It should be taken into account that allogeneic haematopoietic stem cell transplantation is the less frequent alternative in PNH patients (22).

B. Critical analysis of information submitted by the company

Economic information submitted by the company did not include pharmacoeconomic evaluation of treatment with eculizumab nor the detailed budget impact for Andalusia. Information provided included:

• Estimation of annual cost of the treatment in terms of retail price, under the assumption that total cost would consist of HPP + VAT. It was stated that budget impact would amount to 0.51% regarding the total health, but this particular datum was not warranted. In the same way, the existence of potential saving was mentioned, both in direct and indirect costs derived from drug use, but remained unquantified.

• Survival analysis. For this analysis two assumptions were made, as there is no evidence was presented to suggest that eculizumab will provide survival results. The first assumption presumed a median survival from diagnosis between 10 and 22 years. In the second case, median survival was estimated between 22 and 30 years. In both cases it was also assumed a constant mortality rate through time. From these data, the company established 4 different scenarios (best and worst scenario for eculizumab in a combined manner) in which better survival after 20 years ranged from 0%-50%.

• From a methodological point of view, survival analysis accomplished, though interesting, it lacks limitations derived from the assumptions made, that reduce the degree of validity of the results given. Firstly, median survival from diagnosis of 10-22 years is excessively optimistic, as best quality available


48 >

bibliography places it between 10-14.6 years (1). Mortality rate is not maintained constant through time: in the first ten years after diagnosis, rate is significantly greater (4).

• Analysis of the necessary number of patients to treat (NNT) to obtain different clinical results.

For the reduction of thrombotic events, company concluded that NNT was of 2 (absolute risk reduction 62%). However, it must be taken into account that data were based on a non-controlled intervention study, in which patients enrolled through different stages in time. In the different studies, time period elapsed from diagnosis of PNH to starting treatment varied from a median of 4.9 and 8.7 years. While the mean period after starting treatment was just of 1.4 years. This means that number of thrombotic events were compared among quite irregular temporal periods. Thus, to estimate the NNT, it is necessary to use the thrombotic events rate, instead the number of thrombotic events.

In the case of absence of PRBC transfusions requirements, information provided (NNT=3) was not correct, as risk was reduced in a 51 % (NNT=2).

To attain haemoglobin levels stabilization, NNT provided by the company was inferior to real (2 vs. 3).

In the case of NNT, to achieve relevant differences in the quality of life measured by FACIT-Fatigue scale, NNT was of 4, what coincides with the one subsequently calculated in this report.

C. Economic analysis de novo

There are different estimations of cost-efficacy ratios for clinically significant markers evaluated in the studies. These estimations were accomplished using the results of the efficacy and safety systematic review.

In the same way, estimations of the budget impact for the SSPA have been made according to the number of PNH patients who would be treated with in different scenarios.

Information base • Population in Andalusia: 8,389,271 inhabitants (23).

• Prevalence of PNH: 0,55 cases/ 100,000 inhabitants (24)

• Cost of treatment with eculizumab (HPP + VAT) (10):

- First year: 377,182.00 €

- Second year and subsequent: 360,984.00 €

• Cost of each PRBC: SAS pricing: 73.88€ (25). Figure updated on February 2010 (general variation on the RPI 8.5%).

Cost-efficacy ratios

Cost of life year gained

There is no evidence about the impact of eculizumab treatment on survival


< 49

improvement in patients with PNH. In consequence, it is not possible at present to estimate life years gained with treatment.

Cost of thrombotic events reduction

Efficacy results in terms of reduction of thrombotic events rate belong to a poor quality study, so it is impossible to estimate the real magnitude of that reduction. When considering data from the extension study, despite its poor quality, it is observed that reduction of thrombotic events would be around 7.37/100 patients/year to 1.07/100 patients/year. This would be an absolute reduction of 6.30 events per 100 patients/year, that is, 16 patients should be treated in a year in order to avoid one thrombotic event during that year.

Annual cost to avoid one thrombotic event in a year:

16 377,182.00€ = 6,034,912.00 €

Corresponding annual cost of eculizumab drug in the first year of treatment.

Coste para mejorar la calidad de vida

In TRIUMPH RCT, 53.7% of patients in eculizumab group showed a shift in the FACIT-Fatigue scale ≥ 4 scores (minimal clinically important difference) with respect to 20.5% of patients in the placebo group (p=0.0028) (8). This means a NNT of 4 (IC 95%: 2-8). In consequence, it is necessary to treat 4 patients to achieve a clinically relevant improvement of quality of life (measured FACIT-Fatigue scale) in one of them.

Cost of quality of life improvement in one patient after six months:

1,508,728 € (754,364 – 3,017,456 €).

It must be taken into account that patients’ baseline scoring data in the scale were not indicated, and the marker was not an intention to treat analysis.

Cost per each PRBC unit avoided

Las UCH evitadas por el tratamiento con eculizumab se obtuvieron a partir de los estudios TRIUMPH y SHEPHERD. Se utilizaron las medianas de UCH al no seguir esta variable una distribución normal.

PRBC units avoided due to eculizumab treatment were estimated from TRIUMPH and SHEPHERD studies. Medians of PRBC units were used, as this marker does not follow a normal distribution.

TRIUMPH RCT Median of transfused PRBC units in the placebo group was 10 vs. 0 in the

eculizumab group, after 6 months.

Cost of each PRBC unit avoided in 6 months = 19,669.00 €

It must be taken into account that this cost is applied when a patient receives 9 PRBC units instead of 10 PRBC units, during 6 months (1.7 vs.1.5 PRBC units


50 >

transfused/month).

Considering patients stratification according to transfused PRBC units in the previous 12 months before treatment, median differences of PRBC units among placebo and eculizumab groups, after 6 months treatment, were calculated.

Table 10. Cost per PRBN avoided according to the study TRIUMPH

PRBC units prior to

treatment

Median PRBC units transfused after 6 months ECULIZUMAB

Median PRBC units transfused after 6 months

PLACEBO

Difference Cost per averted prbc unit after 6

months

4 - 14 0 6 6 32,781.67 €

15 - 25 2 10 8 24,586.25 €

> 25 3 18 15 13,112.67 €

SHEPHERD study According to results provided by this study, the median of transfused PRBC units

diminished from 8 to 0 after 52 weeks of eculizumab treatment. Patients of this study required less amount of previous PRBC units transfusions than patients in the TRIUMPH RCT.

Cost of each PRBC unit avoided in 1 year = 47,147.75 €

Considering patients stratification according to LDH levels when starting eculizumab treatment, median differences of PRBC units after 12 months treatment were calculated.

Table 11. Cost per PRBN avoided according to the study SHEPHERED

Previous LDH levels (U/L)

PRBC units transfused prior to treatment (median)

PRBC units transfused after

treatment (median) Reduction

Cost per PRBC unit averted

537 - 1379 8.00 0.00 8.00 47,147.75 €

1380 - 2050 7.50 1.00 6.50 58,028.00 €

2051-2866 9.50 0.50 9.00 41,909.11 €

2867 - 5245 8.50 2.00 6.50 58,028.00 €


< 51

Annual cost for a patient to avoid transfusions during six months

In the TRIUMPH RCT, 51% of patients in the eculizumab group was transfusion-independent during 6 months against 0% in the placebo group. Thus, the NNT is 2 (IC 95%: 2-3), that is, it is necessary to treat 2 patients for one of them to avoid transfusions.

Annual cost for a patient to be transfusion-independent during six months = 754,364.00€ (754,364.00€ -1,131,546.00 €)

Annual cost applied correspond to the first year of treatment.

Budgetary impact for SSPA

Estimate of budget impact has been limited to a time horizon of one year, as there are no efficacy date of eculizumab treatment in longer periods of time.

Different scenarios have been considered, accordingly to the different estimates of cases that would be treated.

Table 12. “Scenarios” of eculizumab use

Scenario Description

A

All patients accomplishing indication criteria approved in the technical data sheet would be treated. To calculate the number of cases it is estimated a prevalence of 0.55 cases/100,000 inhabitants (24)

B and C

Between 16% and 33% of patients with PNH (1) could be treated, according to international experts . To calculate the number of cases it is estimated a prevalence of 0.55 cases/100,000 inhabitants (24)

D According to region experts’ opinion, in Andalusia, 25 patients with PNH could be candidates to be treated with eculizumab.

E Patients in which treatment is more cost-effective.

Table 13. Number of cases and scenarios impact

Scenarios Cases/ year Annual cost

A. Technical data 46 17,350,372.00 €

B. 16% patients with PNH 7 2,640,274.00 €

C. 33% patients with PNH 15 5,657,730.00 €

D. Clinical experts opinion 25 9,429,550.00 € E. According TRIUMPH RCT 25 E.1 4-14 PRBC required 9 3,394,638.00 € E.2 15-25 PRBC required 10 3,771,820.00 € E.3 >25 PRBC required 6 2,263,092.00 €

Health expenditure reflected in the 2006 SAS Report (26) increased to 2,976,446,295.52 € (3,134,197,949€, updated in 2010, general variation on RPI rate


52 >

5.3%). From this datum the budget impact of health expenditure may be calculated, and would range between 0.07% and 0.55%, depending on the scenarios with less or more treated patients, respectively.

In TRIUMPH RCT, the median of transfused PRBC units in the placebo group was of 10 vs. 0 of the eculizumab group, after 6 months. It was estimated the annual cost of averted PRBC units transfused in the different scenarios taken into account accordingly to cases susceptible of treatment. Thus, it was assumed that reduction of PRBC units transfused median differences remain steady for a year.

Table 14. Annual savings for each scenario

Scenario according to cases susceptible of being treated in Andalusia

Annual saving due to reduction of PRBC units transfused

A. Technical data 67,967.44 €

B. 16% patients with PNH 10,342.87 €

C. 33% patients with PNH 22,163.30 € D. Clinical experts opinion 36,938.83 € E. According TRIUMPH RCT E.1 4-14 PRBC required 7,978.79€ E.2 15-25 PRBC required 11,820.42€ E.3 >25 PRBC required 13,297.98€


< 53

Discussion

1. Efficacy and safety systematic review discussion

Evidence available on eculizumab is still very limited in terms of clinical endpoints measured in trials, monitoring follow-up, and number of patients. However, it must be taken into account that the recent commercialization of this drug, as well as the fact of being an ultra-rare disease treatment, justify these limitations.

Survival

Until end date of this systematic review no evidence was found that treatment with eculizumab improves survival in PNH patients.

Thrombotic events

Risk reduction of thrombotic events is, after an improvement in survival, one of the most relevant clinical endpoints in patients with PNH, as thrombotic events are the leading cause of death. In Hillmen et al. extension study(18), incidence of thrombotic events rate prior to eculizumab treatment almost doubled the incidence rate published in the systematic review of the natural history of PNH by Connock et al, in patients who had not received treatment with eculizumab (1). This difference between incidence rates of thrombotic events may be due to the fact that only 73% thrombotic events, in Hillmen et al. study, could be objectively identified, therefore assuming that this rate could be overvalued.

In the same study (18), when thrombotic events incidence rate is evaluated in patients receiving previous antithrombotic treatment, it increases considerably. This is almost certainly due to the fact that patients with prophylactic treatment were the most severe cases and also the ones with higher baseline risk of suffering this type of events.

Major limitation of Hillmen et al. study is the absence of a control group, which makes impossible to assess whether the effect on the reduction of thrombotic events is due to eculizumab, or to other interventions such as concomitant anticoagulation therapy, or non-controlled factors. In this sense, Hall et al. (27) data suggest that prophylactic antithrombotic therapy is effective in the prevention of events in PNH patients. The cumulative incidence rate of thrombotic events was 0 events/100 patients-year in patients treated with prophylactic antithrombotic therapy vs. 3.7 events/100 patients-year in treatments without prophylaxis.

Monitoring period of TRIUMPH RCT (26 weeks), is not sufficient to obtain conclusions on eculizumab efficacy in the prevention of thrombotic events.

In short, there is no clear evidence that eculizumab reduces the number of thrombotic events. It is necessary to attain good quality studies, in order to evaluate eculizumab efficacy in the incidence of thrombotic events, with an accurate monitoring period, and bring solid evidence to this aspect.


54 >

Quality of life

Quality of life improvement is a fundamental parameter in the evaluation of treatments of disabling diseases such as PNH. However, quality of life gaining is a subjective endpoint which is also dependant on the scale used. Likewise, taking into account that quality of life in closely related to other markers such as RBC administration, anemia, etc, which can be evaluated in an objective manner, it could be possible to determine which marker is most clinically significant.

In the TRIUMPH RCT (16), the mean change in the scoring of the FACIT-Fatigue scale in quality of life was greater than in eculizumab patients. However, within more frequent adverse events in patients of TRIUMPH RCT, it was observed that 12% of patients treated with eculizumab showed fatigue versus 2% of patients treated with placebo. In the SHEPHERD study (17), mean scoring of FACIT-Fatigue scale also improved significantly after eculizumab treatment. Notwithstanding, as baseline scoring in the patients’ quality of life questionnaires was unknown, both in TRIUPMH and SHEPHERD studies, it is not possible to compare improvement in quality of life of eculizumab treatment with the general population [(mean scoring of FACIT-Fatigue scale in general population is 40.1 ± 10.4 (28)].

In relation to global health status in the different studies, there were improvements in scoring shifts in most of evaluated items. However, only EORTC QLQ-C30 baseline scoring of pilot study (14;15) are available. Mean baseline scoring was 56.1, and shift after 64 weeks of treatment was 13.8(p=0,009)(15). That is, patients with PNH improve scoring in global health status, but they do not achieve mean scores of general population[76, approximately (29;30)].

In relation to fatigue, patients in pilot study extension showed a mean baseline scoring of 47.5 and shift after eculizumab treatment was of -17.8 (p<0,001) (15) (better results imply low scoring, so, the closer to 0 less fatigue). For all this, patients with PNH achieve improvement in fatigue scores, but they do not reach the mean scorings of general population[16 (Sweden) (29) y 20 (Germany) (30)].

Transfusions requirements

TRIUMPH RCT provides best evidence that eculizumab treatment significantly reduces need for RBC transfusions in patients with PNH, with very similar results to that of the SHEPHERD study. However, despite reduction in the median of number of transfused PRBC are statistically significant, almost half of the patients (49%) under eculizumab treatment still require transfusions, both in TRIUMPH RCT and SHEPHERD study (16;17). Besides, in SHEPHERD study(17), the percentage of patients free of PRBC transfusions could be overvalued, as there were patients who did not received transfusions in the previous 12 months before the study (see Table 2).

In the stratified analysis of TRIUMPH RCT, patients treated with eculizumab vs. placebo achieved significant reduction of PRBC units transfused (8). However, in groups with greater transfusions requirements before study, patients achieved major reductions in PRBC requirements.

In the stratified analysis of SHEPHERD study (17), according to baseline levels of LDH, only patients with levels of LDH superior to 1,380 U/L, could reduce significantly the number of transfused PRBC units.


< 55

In conclusion, treatment with eculizumab reduces PRBC units transfusion requirements versus placebo, being patients with moderate to severe type of disease (according to transfusion requirements and haemolysis) the ones obtaining more benefits.

Safety

Eculizumab treatment is generally well tolerated by patients with PNH.

Incidence of meningitis is higher in patients treated with eculizumab than in normal population. It is important to highlight that, despite vaccination before eculizumab treatment is recommended, N. meningitidis serogroup more prevalent in Spain is serogroup B, which has no vaccine at present. In Spain, incidence of N. meningitidis B within general population was of 1.19 cases/100,000 inhabitants during the years 2004-2005 (31); while estimated incidence of meningitis in patients with eculizumab treatment is of 500 cases/100,000 patients (32).

In relation to the risk of haemolysis crisis upon withdrawal of eculizumab treatment, both TRIUMPH RCT and SHERPHED study show an increase of PNH erythrocytes type III (16;17). These results indicate a reduction of haemolysis in patients treated with eculizumab, and provide a biological plausibility of considering a potential risk of serious haemolytic episode if eculizumab treatment is interrupted. Notwithstanding, published data show that 16 patients withdraw from treatment during the studies (3;8;33). This patients were monitored during 8 weeks at least after withdrawal from eculizumab treatment, and no haemolytic episodes were observed (3;33).

Nevertheless, eculizumab has recent comercialization, so there is no long-term evidence of safety in its administration.

Restarting of eculizumab treatment

There is no evidence of efficacy and safety of restarting eculizumab treatment upon withdrawal, in PNH patients.

Efficacy and safety during pregnancy

In general, IgG may pass through the placenta, though IgG2 structucture is more problematic to pass through it. Eculizumab is a formulation which is a recombinant humanized monoclonal IgG2/4 kappa immunoglobulin, so crossing the placenta is improbable. However, in animal testing it has been observed that eculizumab can cross the placenta. Due to the absence of quality studies in pregnant patients with en PNH, eculizumab has been included in pregnancy category C C (34).

Published evidence regarding pregnant women is limited to a series of 6 patients. One of the patients underwent an elective abortion, one patient received eculizumab during the whole pregnancy, one started treatment in 27th week of pregnancy, and three patients received eculizumab from the beginning and until 4-16 weeks of gestation. The latter three interrupted treatment, as trial excluded pregnant women.

Any of the pregnant women suffered adverse events, though one of them


56 >

required an adjustment of the posological interval (from 14 to 12 days), as a result of an increase of haemoglobinuria and abdominal pain. All babies were healthy (34-36).

In short, evidence of eculizumab usage in PNH patients during pregnancy is of poor quality.

Efficacy and safety in patients under 18

No evidence was found of efficacy and safety of eculizumab treatment in patients under 18.

Efficacy and safety in patients de novo (who did not received previous transfusions)

No evidence was found of efficacy and safety of eculizumab treatment in patients de novo.

Sytematic review results in comparison with other systematic reviews

The results of this sytematic review are consistent with the results published by Connock et al. (1). These authors declared that, in general terms, eculizumab treatment reduced haemolysis, PRBC requirements, and anemia. Besides, quality of life also improved after treatment with eculizumab, mainly in relation to fatigue.

Connock et al. (1) concluded that eculizumab treatment reduced the thrombotic events rate in patients with PNH. In contrast, authors of this systematic review, after the evaluation of the literature and its quality, consider that evidence related to eculizumab efficacy on thrombotic events reduction, has not enough quality as to claim that eculizumab reduces the thrombotic events rate in patients with PNH.

Limitation of the systematic review of efficacy and safety

A systematic review of efficacy and safety of eculizumab in the PNH, has been accomplished based on the best evidence available. Nevertheless, only a RCT estimating eculizumab efficacy and safety in PNH patients was found in the literature.

2. Review of the economic analysis

Some international organisms establish parameters from which a certain clinical technology is not cost-effective. In Spain, that limit is around 30,000€ and 50,000€ per adjusted life year gained (QALY) (37). Above that amount it is considered that technology is economically unsustainable by the public health system. In the case of ultra-orphan drugs, quite above budget thresholds, QALYs had been reconsidered in order to obtain a final cost per QALY similar to normal thresholds. The National Institute for Clinical Excellence (NICE) (38) suggested that decision on incorporation of ultr-orphan drugs to health systems, must be based on cost-effectiveness ratios of those ultra-orphan drugs


< 57

that are already commercialized. In this sense, the NICE establishes the range £200,000 and £300,000 per QALY.

Up to the present, however, scientific evidence does not prove that eculizumab improves survival in treated patients, but only that surrogate endpoints are improved, so it is not possible to estimate a cost per QALY, even less the aforementioned discussion. Even if considering those thresholds as estimates applicable to cost-efficacy ratios (correspondant to those surrogate endpoints), these are too superior. Thus, the annual cost of improving the quality of life (measured by FACIT-Fatigue scale) of a patient after 6 six months is approximately of 1,500,000€/ year. In the case of reduction of thrombotic events (most clinically relevant surrogate endpoint) annual cost to avoid one event in a year, in the best-case scenario, it is above 6,000,000€ (120 times the higher threshold to increase life expectancy by a year; and 20 times over the maximum figure established by the NICE for ultra-orphan drugs).

In a theoretical exercise considering the best scenario for eculizumab, the following premises are assumed for this drug:

• That survival levels of all treated patients equal the general population.

• That suffering PNH for 25 years reduces life expectancy in 10.2 and 4.5 years.

• That all patients under treatment are young.

• That drug works well in all patients.

Cost per life year gained would range from 884,000€ and 2,000,467€, what increases between 2 and 6 times the economic previsions established by the NICE for ultra-orphan drugs. The Canadian Agency for Drugs and Technologies in Health (CADTH) estimates an incremental cost per QALY of 2.4 million dollars which, considering benefits in the long run, could be reduced, but never under 500,000$. That is why this Agency does not recommend that eculizumab should be included in their health system (39).

It is necessary to point out that the minimum incremental cost-efficacy obtained for this drug is of 19,669€, which is also the cost of avoiding one PRBC unit after 6 months (the sum for a patient to receive 9 PRBC units instead of 10 PRBC units, after 6 months). This ratio improves when there is a greater number of transfused PRBC units the 12 months prior to treatment: it decreases until 13,112€ per avoided PRBC unit in those patients whose previous transfusion requirements surpassed 25 PRBC units.

In the case of thrombotic events, the annual cost for avoiding one death due to thrombosis would be superior to 13,000,000€, according to the information submitted by the industry, establishing that half of the patients die as a consequence of these events, and assuming that 1 out of every two thrombosis was mortal (worst scenario).

There is still no estimation of budget impact in a time horizon superior to a year, as there are no efficacy data of eculizumab for longer periods of time.

The annual cost of treatment with eculizumab for the SSPA, in different scenarios according to various estimates of the number of cases to be treated with eculizumab, has been calculated. The aforementioned costs range from 2,263,092€, in the scenario with less amount of cases, to 17,350,372€ in the most populated scenario. Savings related to costs averted by la reduction of transfused PRBC units would range from 13,298€ to


58 >

67,967€, respectively.

From this perspective, budget impact of treatment with eculizumab would range between 0.55% and 0.07% of SSPA total health expenditure, depending on cases treated: all patients (0.000006% of Andalusian population) or just patients in which drug has better cost-effectiveness (0.000003% of Andalusian population), respectively.

Limitations of the economic analysis

Among major limitations to the economic analysis provided, the following are highlighted:

• Surrogate endpoints have been used.

• There is no exact data available in Andalusia for the number of cases that could be treated with eculizumab, as there is no an appropriate register. Estimates regarding published data in the scientific literature have been accomplished, and those estimates have been considered by expert clinicians in Andalusia, obtaining similar results than the estimates of prevalence at national level.

• It is assumed that duration of drug efficacy is sustained through time (TRIUMPH RCT provides results of 26 weeks, and best results are extrapolated to 52 weeks).

• Possible social and health benefits derived from reduction in rates of thrombosis had not been considered.


< 59

Conclusions

1. There is no evidence that treatment with eculizumab increases survival in PNH patients.

2. Evidence of eculizumab in diminishing the probability of thromboembolic events is not of sufficient quality. As a result of this, it is not possible to arrive at definite conclusions about the reduction of thromboembolic events in PNH patients. It is necessary to develop high quality studies contributing to solid evidence regarding this matter.

3. Half of PNH patients receiving eculizumab treatment show FACIT-Fatigue scores increased by four points in this instrument scale, especially when related to fatigue grade (minimum clinically important difference in quality of life).

4. Eculizumab treatment in PNH patients reduces the number of PRBC transfusions requirements when compared with placebo. Patients avoiding more PRBC transfusions are the more severely affected patients or the moderate affected (depending on pre-treatment transfusion requirements and haemolysis).

5. Eculizumab treatment in PNH patients diminishes haemolysis (measured through LDH levels). The reduction in LDH levels with eculizumab commenced within one month and levels remained constant during the treatment period.

6. Eculizumab treatment is generally well tolerated.

7. Patients with eculizumab therapy show a higher incidence of N. meningitidis compared with general population. In consequence, patients must be vaccinated when receiving eculizumab. However, the vaccine is not effective against serogroup B of N. meningitidis, being this the most prevalent serogroup in Spain, and the one producing more infections.

8. There is no evidence for long-term safety of eculizumab in PNH patients.

9. There is no evidence regarding efficacy and safety when PNH patients resume eculizumab treatment after withdrawal.

10. There is no quality evidence allowing recommendations for eculizumab usage in PNH patients during pregnancy.

11. There is no evidence of efficacy and safety of eculizumab treatment in patients with PNH who are under 18.

12. No evidence was found for the use of eculizumab in patients with PNH de novo (patients without previous transfusions).

13. Lack of information related to drug effectiveness means that implementation of a full economic assessment for estimation of cost-effectiveness and/or cost-utility is impractical at this time.

14. The budget impact for the SSPA varies according to the different scenarios of cases eligible for eculizimab treatment and was estimated between 0.07% and 0.5% of total hospital expenditure.

15. As there is no scientific evidence regarding survival of treated patients, but just improvement of surrogate endpoints, it is not possible to calculate a model for


60 >

estimation of cost in terms of QALY. According to a theoretical exercise based on significant assumptions, a cost per LYG will exceed between two and six times the highest estimations for ultra-orphan drugs as advised by NICE.

16. Cost-effectiveness ratios estimated for surrogate endpoints of major clinical relevance show very high values (exceeding the highest estimations advised by NICE for this type of drug in terms of the incremental cost per QALY, which could serve as reference).


Recommendations

• The use of eculizumab in PNH patients when there is no evidence should be considered as experimental. These situations include at this moment: patients without a history of transfusions, patients under 18, pregnant patients, and patients who recommence eculizumab treatment after withdrawal.

• Given that there is only solid evidence of eculizumab effectiveness for the surrogate endpoints, transfused PRBC units, and LDH levels, these outcomes should guide the criteria that define those patients who would qualify for eculizumab treatment. There is solid evidence that only patients with a greater history of transfusions in the previous year and higher LDH baseline levels, show major clinical benefit and better relation cost-effectiveness. In consequence, those should be the criteria to select subgroups which potentially will obtain more benefit from treatment. For the rest of patients supportive measures and monitoring are recommended.

• In areas where there is uncertainty about eculizumab efficacy being it measured in terms of health-related outcomes (f. e. reduction of thrombosis rates) it is recommended to establish an agreement based on shared risks with the manufacturing laboratory.

• It is necessary for all patients who enroll for eculizumab treatment to accomplish the Risk Management Plan designed by the EMA for this drug.

• It is recommended to undertake an evaluation of effectiveness and safety after 3 months of treatment. In this initial evaluation, LDH levels will indicate eculizumab effectiveness. In those patients in which eculizumab is not effective and/or safe, it is recommended to withdraw treatment.

• Patients in whom treatment seems to be effective after the three first months should continue periodic monitorisation every six months. The following parameters should be registered: thrombotic events (type and location), number of RBC units transfused, biochemical parameters (LDH and creatinine), haemogram, infections (type and location), disease evolving towards other haematologic pathologies (aplastic anemia, leukaemia or myelodysplasic syndromes), adverse events, and spontaneus remission. Patients in whom eculizumab is not effective and/or safe are recommended to withdraw from treatment.

• It is recommendable that the SSPA creates a group, for the granting of centralised authorisation for this treatment. The group should apply the resolution established by the SAS management, individually, to each potential case. In the same way this group will be responsible for management of patients’ monitoring.

• In addition, it is recommended the foundation of a PNH registry in Andalusia.


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